By Arzo Hamidi, PharmD, BCCP
Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago
SYNOPSIS: In this multinational, population-based cohort study among patients with atrial fibrillation, apixaban use was associated with lower risk of gastrointestinal bleeding with similar rates of ischemic stroke or systemic embolism, intracranial hemorrhage, and all-cause mortality.
SOURCE: Lau WCY, Torre CO, Man KKC, et al. Comparative effectiveness and safety between apixaban, dabigatran, edoxaban, and rivaroxaban among patients with atrial fibrillation: A multinational population-based cohort study. Ann Intern Med 2022;175:1515-1524.
The objective of the study was to compare the effectiveness and safety outcomes between apixaban, dabigatran, edoxaban, and rivaroxaban among patients newly diagnosed with atrial fibrillation (AF). Direct oral anticoagulants (DOACs) are used for stroke prevention with less monitoring required than vitamin K antagonists. Studies have not previously compared the specific DOACs head-to-head. This study used standard databases from four countries (France, Germany, United Kingdom, and United States) that included more than 221 million individuals across different healthcare settings. This was a new-user, active-comparator cohort design that included patients ≥ 18 years of age with AF who never previously received a DOAC. Patients had at least one year of observation in the database prior to enrollment to record medical history, demographics, and other diagnoses. Patients were excluded if there was a history of mitral stenosis, hyperthyroidism, mechanical heart valve replacement, or transient AF. Patients also were excluded if there was a prescription for warfarin within the previous 180 days or another DOAC during the enrollment date.
The outcomes analyzed were incidence of intracranial hemorrhage (ICH), gastrointestinal bleed (GIB), all-cause mortality, or a composite outcome of ischemic stroke and systemic embolism. This study received no drug company-related funding. Specific statistical analysis was conducted to minimize bias. Propensity scoring was used to compare patients who differed in anticoagulant choice. The propensity score models included > 90,000 predefined baseline patient characteristics. Cox proportional hazards regression was conducted to estimate the hazard ratio for the risk of outcomes. Subgroup analysis was completed comparing standard-dose regimens vs. reduced-dose, patients who were 80 years or older, and, lastly, patients with chronic kidney disease (CKD).
In total, 527,226 patients were included, with the highest users being prescribed apixaban and rivaroxaban. Follow-up time varied between 534 and 1,612 days, with the shorter follow-up ranges occurring in the U.S. databases. The mean CHA2DS2–VASc score ranged from 2.8 to 3.9 for apixaban, 2.6 to 3.7 for dabigatran, 2.5 to 3.6 for rivaroxaban, and 2.9 to 3.8 for edoxaban. Baseline characteristics were similar among groups. There was no significant difference between DOACs in the composite of ischemic stroke and systemic embolism, ICH, or all-cause mortality.
Apixaban was associated with a lower risk for GIB than dabigatran (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.7-0.94), rivaroxaban (HR, 0.72; 95% CI, 0.66-0.79), or edoxaban (HR, 0.77; 95% CI, 0.66-0.91). Among patients who received a reduced-dose DOAC, ischemic stroke or systemic embolism rates were lower with apixaban than rivaroxaban (HR, 0.68; 95% CI, 0.46-1.01) and lower with dabigatran than rivaroxaban (HR, 0.67; 95% CI, 0.49-0.94). These associations were not found among standard-dose DOACs. The risk for GIB was lower with apixaban than dabigatran in patients with CKD (HR, 0.71; 95% CI, 0.54-0.94) and lower with apixaban than rivaroxaban (HR, 0.68; 95% CI, 0.59-0.77).
For patients 80 years or older, apixaban was associated with lower risk for GIB than dabigatran (HR, 0.65; 95% CI, 0.44-0.95), rivaroxaban (HR, 0.64; 95% CI, 0.57-0.72), or edoxaban (HR, 0.64; 95% CI, 0.5-0.82).
COMMENTARY
Anticoagulant choice is based on efficacy, safety, and ease of administration and monitoring. As the use of DOACs has increased in the last two decades since their approval, the use of vitamin K antagonists has fallen out of favor because of requirements for patient monitoring. This study is one of the first of this size to compare the DOACs head-to-head, and the authors attempted to minimize bias through robust propensity-matched controls using predefined baseline characteristics and calibration of confidence intervals. This study also maintained adequate follow-up using these national databases. The shortest follow-up of patients, unfortunately, occurred with patients from the United States compared to the other nations.
Overall, apixaban and rivaroxaban were the most used DOACs, which matches practices in the United States. Apixaban anecdotally is thought to be safer than rivaroxaban. This study shows no differences among the DOACs regarding ischemic stroke or systemic embolism, ICH, or all-cause mortality. Overall, the risk of GIB seems to be lower with apixaban compared to the other DOACs. Notably, relevant subgroup analyses were completed for high-risk patients (i.e., patients with CKD or older than the age of 80 years). This showed a lower risk for GIB with apixaban compared to the other DOACs in patients 80 years or older.
In patients with CKD, apixaban was found to have a lower risk of GIB compared to dabigatran and rivaroxaban, but not edoxaban. Of note, the use of edoxaban has been limited in practice because of its unique dosing based on renal function; this also matches the lower number of patients who received edoxaban in this study. It is important to note that bleeding was identified using diagnosis records that did not qualify the severity of bleeds.
While previous studies and postmarketing data previously indicated that the DOACs were safer than vitamin K antagonists and as efficacious, this study brings to light data comparing the DOACs to each other. To continue to answer this question, a prospective, randomized controlled trial with adequate power would be needed comparing these DOACs head-to-head, which would be very difficult to conduct. For now, these results may indicate that apixaban has a lower overall risk for GIB compared to other DOACs with similar rates of other outcomes of safety and efficacy.
In this multinational, population-based cohort study among patients with atrial fibrillation, apixaban use was associated with lower risk of gastrointestinal bleeding with similar rates of ischemic stroke or systemic embolism, intracranial hemorrhage, and all-cause mortality.
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